This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our research goal is to elucidate the molecular details of how microRNA molecules are generated. MicroRNAs are small regulatory RNA molecules that are produced and regulated endogenously throughout development, particularly prominent in eukaryotes. Recent advances in microRNA research has only begun to reveal the importance of their role, as microRNAs control gene expression in various processes of life: MicroRNAs govern processes in stem cell maintenance, cell differentiation, and organism development, which makes their dysregulation linked to many diseases such as various types of cancer. We study the basic steps involved in producing microRNAs in cells. Currently we are focusing on a model microRNA, the family of let-7 microRNAs. The first regulatory molecule in microRNA biogenesis, LIN-28, was found to specifically block maturation of precursors of let-7. LIN28 specifically interacts with the let-7 precursor, preventing its processing by Drosha and/or Dicer enzymes. However, how various let-7 members are recognized and how the binding event leads to protection from RNAses that cleave at opposite ends of the precursor is still unclear. By understanding the structural details of the interaction of LIN28 with precursor let-7, we will gain insight into how microRNA precursors are recognized by the RNAses for proper maturation.